A major effort in the laboratory is devoted to understanding dystonia. Our fundamental view is that there is a deficiency of inhibition in central nervous system mechanisms in dystonia. Specifically, an important type of defective inhibition is surround inhibition, where muscles and movements not desired for the task need to be inhibited. Lack of inhibition leads to motor overflow and action dystonia. We are trying to identify specific inhibitory circuits that contribute to surround inhibition. Studies are first done in normal subjects and then in patients. We have investigated a variety of inhibitory mechanisms already, and we are now engaged in understanding the premotor to motor cortex interactions and parietal to motor cortex interactions in focal hand dystonia. Recent evidence suggests that the final part of the mechanism of surround inhibition actually arises from the connections within the motor cortex itself. We have also explored surround inhibition during tonic movement and have determined that cerebellar pathways play a role. Recent studies include the EEG response to TMS and checking its response with surround inhibition. We are also exploring the physiology of motor learning in dystonia. Motor learning seems disturbed, and seems to have a principal role in producing focal hand dystonia since long term repetitive activity is certainly an etiological factor. In one type of experiment, we have been evaluating brain and spinal cord plasticity using brain and nerve stimulation paradigms. We have concluded a case-control experimental study to evaluate long-term learning of sequential finger movements in focal hand dystonia patients, and are analyzing the data now. We are also investigating the mechanism of sensory tricks. We have recently completed a series of studies looking at dopamine signalling in focal hand dystonia and laryngeal dystonia. Findings include decrease of D2 receptors and increase in D1 receptors in the putamen, the motor part of the basal ganglia. There is also a decrease in the amount of dopamine release with movement in these patients. To gather further evidence for abnormalities in dystonia we are also exploring evidence for anatomical changes and for a deficiency of GABA-ergic mechanism. We are doing MRI studies with voxel based morphometry (VBM), diffusion tensor imaging (DTI), GABA magnetic resonance spectroscopy (MRS), anatomical imaging at 7 tesla, flumazenil PET studies and pathological studies of brains of patients with dystonia. We have done a comprehensive study of histopathology of brains from patients with DYT1 dystonia and not found any obvious pathology. There is also evidence for cholinergic abnormality in dystonia. We have found decrease of cholinergic markers in the pedunculo-pontine region in a pathological study of cervical dystonia, and are now doing a PET study with a cholinergic ligand. The genetic markers in focal dystonia are largely unknown. We are cooperating with the multisite NIH sponsored Dystonia Coalition for work in this area. In regard to the Dystonia Coalition, we are also participating in studies developing new scales for the diagnosis and severity of blepharospasm. We are also exploring further the physiology of Parkinson disease (PD). Although the sequence effect, the gradual reduction in size of movement, is one of the most common symptom in PD, its characteristics and etiology are largely unknown. With objective measurement, we have completed some studies of the clinical features and the lack of beneficial effect of levodopa and repetitive transcranial magnetic stimulation, and we are now evaluating the behavioral features and neuroimaging correlates. MRI findings suggest that the sequence effect is related to the energetic cost of movement. We are also studying gait freezing that, at least in some circumstances, relates to the sequence effect. One project in this regard is to use eyetracking to determine where patients look while they walk. For patients with Parkinson disease, we have an active DBS program. We are analyzing DBS electrode placement for those patients that do well and those that have side effects. In an additional collaboration with the Surgical Neurology Branch, we are in the follow-up phase of a safety study of an infusion of AAV2-GDNF in the putamin of patients in order to support dopaminergic neurons.